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Drug-Induced Nephrotoxicity: Clinical Impact and Preclinical in Vitro Models

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Yong Loo Lin School of Medicine, National University Health System, 1E Kent Ridge Road, NUHS Tower Block, Singapore 119228, Singapore
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, Singapore 138669, Singapore
*A.V.: phone, +65 67726124; fax, +65 67794112; e-mail, [email protected]
*D.Z.: phone, +65 6824 7107; fax, +65 6478 9080; e-mail, [email protected]
Cite this: Mol. Pharmaceutics 2014, 11, 7, 1933–1948
Publication Date (Web):February 6, 2014
https://doi.org/10.1021/mp400720w
Copyright © 2014 American Chemical Society

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    Abstract

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    The kidney is a major target for drug-induced toxicity. Drug-induced nephrotoxicity remains a major problem in the clinical setting, where the use of nephrotoxic drugs is often unavoidable. This leads frequently to acute kidney injury, and current problems are discussed. One strategy to avoid such problems would be the development of drugs with decreased nephrotoxic potential. However, the prediction of nephrotoxicity during preclinical drug development is difficult and nephrotoxicity is typically detected only late. Also, the nephrotoxic potential of newly approved drugs is often underestimated. Regulatory approved or validated in vitro models for the prediction of nephrotoxicity are currently not available. Here, we will review current approaches on the development of such models. This includes a discussion of three-dimensional and microfluidic models and recently developed stem cell based approaches. Most in vitro models have been tested with a limited number of compounds and are of unclear predictivity. However, some studies have tested larger numbers of compounds and the predictivity of the respective in vitro model had been determined. The results showed that high predictivity can be obtained by using primary or stem cell derived human renal cells in combination with appropriate end points.

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